PROJECT SUMMARY Permanent neurologic disability in the major demyelinating disease in human, Multiple Sclerosis (MS), is thought to be primarily due to the degeneration of chronically demyelinated and hence more vulnerable axons. Thus, remyelination represents a critical therapeutic objective for restoring neurologic function in MS. However, there are, at present, no practical approaches available that lead to the regeneration of myelin in vivo in the human brain. One difficulty in identifying such therapeutic regeneration-promoting approaches lies in the currently still limited knowledge about the molecular mechanisms that regulate the differentiation along the lineage of the myelinating cells of the central nervous system (CNS), namely oligodendrocytes (OLGs). Interestingly, progenitors with the capacity to differentiate into mature OLGs have been found present within the MS CNS. However, they fail to mature for reasons that are currently not fully understood. Thus, a promising approach toward a curative and myelin restoring therapy lies in the characterization of molecular signaling axes that can promote developmental OLG differentiation but are misregulated within the MS CNS. In this regard, our recent studies identified the glycoprotein autotaxin (ATX), also known as ENPP2, PD-I?/ATX or lysoPLD, as an extracellularly located factor that can stimulate OLG differentiation during development. In MS, on the other hand, ATX mRNA and protein levels have been found reduced within the CNS parenchyma. In addition, our recent data have identified ATX's enzymatic lysophospholipase D (lysoPLD) activity, known to generate the lipid signaling molecule lysophosphatidic acid (LPA), as the mediator of ATX's functions on the early stages of the OLG lineage. Importantly, our recent data showed that ATX's lysoPLD activity exerts its effects via the stimulation of histone deacetylation, an epigenetic mechanism that has been well-demonstrated to be crucial for OLG differentiation. Notably, a shift toward a decrease in histone deacetylation has been implicated in contributing to the limitations in myelin repair seen in MS. Thus, the ATX-LPA axis represents an attractive candidate for a signaling axis that can promote developmental OLG differentiation but is misregulated within the MS CNS. For the present proposal we designed a set of studies that are aimed at establishing the ATX-LPA axis as a crucial regulator of OLG differentiation as well as CNS remyelination. More specifically our studies are set under the central hypothesis that the ATX-LPA signaling axis regulates OLG differentiation via epigenetic modulation through histone deacetylation as well as LPA receptor signaling, and that deficiency in this ATX-mediated mechanism leads to inefficient repair of the myelin sheath. In the long- term, the proposed studies are anticipated to lead to the development and testing of functionally active compounds that target the ATX-LPA axis and may have therapeutic potential for stimulating CNS myelin regeneration under pathologic conditions as they are seen in MS.